Despite the well known addictive and harmful effects of nicotine, epidemiological and experimental studies have shown that nicotine is neuroprotective. Specific schedules of nicotine administration produce different behavioral and physiological effects. We propose that this distinct behavioral and physiological states correspond to different degrees or modes of nicotine-mediated neuroprotection. To test this hypothesis, the susceptibility to neural injury will be assessed in brain slices from rats subjected to various nicotine pretreatments. The injury will be induced by N-methyl-D-aspartate (NMDA), a drug that induces stroke-like neural damage. Besides nicotine, cigarette smoke contains many compounds of unknown activity, including cyclic terpenoid5 called cembranoids. Our group discovered that cembranoids from Puerto Rico marine organisms, as well as those from tobacco, inhibit neuronal nicotinic receptors and also are capable of modifying the behavioral effects of nicotine. In the present project cembranoid effect on the behavioral and neuroprotective effects of nicotine will be analyzed. Signal transduction pathways involved in nicotine-induced neuroprotection, will be studied in pure and mixed cultures of hippocampal cells. mRNA differential display will be performed to search for genes whose expression is induced by nicotine treatment. In addition, the role of nitric oxide and neurotrophins will be assessed. These experiments will be done in collaboration with the group of Dr. Jean De Vellis at the University of California Los Angeles.